Project Summary Hypertension is the leading risk factor for global morbidity and mortality as a primary contributor to coronary artery disease, heart failure, chronic kidney disease, and stroke. Emerging evidence suggests an important role for inflammation and adaptive immunity in the development of hypertension, particularly CD4+ T cells, CD8+ T cells, gamma delta T cells, and B lymphocytes. Interleukin-21 (IL-21) is an inflammatory cytokine produced by CD4+, CD8+, and gamma delta T cells that binds the IL-21 receptor to coordinate pro-inflammatory functions of T cells, B cells, and non-immune cells. Preliminary results demonstrate that IL-21 deficient mice exhibit blunted hypertension associated with decreased T cell cytokine production and B cell immunoglobulin secretion. However, the cellular source and targets by which IL-21 promotes hypertension are unclear. Studies within this proposal will test the hypothesis that IL-21 released by CD4+ T cells promotes the development of hypertension and end-organ damage through direct effects on T and B cells to enhance renal sodium reabsorption. This hypothesis will be addressed by: 1) determining the relative contribution of IL-21 release from CD4+, CD8+, and gamma delta T cells in the development of hypertension and resultant end-organ damage, and 2) determining the importance of IL-21 signaling in hematopoietic and non-hematopoietic cells in the pathogenesis of hypertension, associated end-organ dysfunction, and renal sodium reabsorption. These studies will reveal critical pathophysiological mechanisms by which IL-21 promotes hypertension as a potential master cytokine and novel therapeutic target.